Vestibulotoxicity following aminoglycoside antibiotics and its prevention.

It has been assumed that aminoglycoside-induced damage to the vestibular inner ear ('vestibulotoxicity') is solely due to the inhibition of mitochondrial protein synthesis. There is now substantial evidence, however, to suggest that this form of neurotoxicity is due, at least in part, to the production of free radicals; either in response to excessive stimulation of the N-methyl-D-aspartate (NMDA) receptor by aminoglycosides, or from the formation of oxidative compounds following the binding of aminoglycosides to iron. If activation of NMDA receptors by aminoglycosides contributes to this hair cell death, it should be possible to modify the chemical structures of the aminoglycosides in ways that minimize the unwanted action. Researchers are also currently evaluating drugs that could be co-administered with aminoglycosides in order to interfere with the apoptotic cascade. For example, NMDA receptor antagonists, nitric oxide synthase inhibitors, caspase inhibitors, neurotrophins and free radical scavengers have been demonstrated to protect against aminoglycoside-induced vestibulotoxicity in experimental studies. The next step will be to pursue these effects using in vivo models and drugs that are likely to have favorable pharmacokinetic and side effect profiles in humans.